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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer is the second leading cause of male death from malignant disease in Europe and in the USA. Failure to prevent or eliminate metastatic dissemination is a fundamental problem underlying the current inadequate treatment of prostate cancer, and novel therapeutic strategies are required if this disease is to be successfully managed. No independent markers are yet available to predict the behaviour of any individual prostate cancer, particularly its potential to metastasize, and there is now an urgent prerequisite to identify and characterize genes specifically involved in determining the metastatic phenotype of prostate cancer cells before any biologically appropriate treatment modality can be devised. To identify DNA sequences that trophically promote the metastatic phenotype, we have established a new transfection assay with which to monitor activity of prostate cancer genomic DNA. Rat prostatic G and AT6.1 cell lines derived from the same original Dunning R3327 rat prostatic carcinoma exhibit, respectively, low- and high-metastatic phenotypes when grown in syngeneic Copenhagen rats. Rat mammary epithelial cell line 'Rama 37' derived originally from Wistar-Furth rats yields benign non-metastasizing adenomas when inoculated subcutaneously into syngeneic animals. In this report, the Rama 37 cell line is successfully used as the recipient cell-line for transfected DNA fragments extracted from rat prostatic carcinoma G and AT6.1 cells. New metastatic variants of Rama 37 cells have been generated. Enzymatically fragmented genomic DNA from rat metastatic prostate carcinoma cell lines was co-transfected together with plasmid pSV2neo into parental Rama 37 cells, followed by culture in the presence of Geneticin-G418 to select for the transfected cells. To enable subsequent identification of metastasis-promoting DNA sequences, the fragmented genomic DNA sequences were covalently attached to specifically engineered linker DNA molecules to flank the genomic DNA before transfection. Thereafter, the resulting transfectants were pooled and inoculated into mammary fat pads of female Wistar-Furth rats. Metastases produced by the transfectant cells in vivo were reestablished from secondary tumours and probed for the presence of the specific synthetic oligonucleotide sequences that flanked, and hence identified, the presence of the transfected DNA. These new metastatic cells are shown to provide a sensitive assay system with which to detect DNA sequences responsible for conveying the metastatic phenotype of prostate cancer when inoculated into syngeneic rats.
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PMID:Generation of metastatic variants by transfection of a rat non-metastatic epithelial cell line with genomic DNA from rat prostatic carcinoma cells. 946 Oct

To understand the skeletal metastatic pattern of non-small cell lung cancer, we developed a stable high-expression green fluorescent protein (GFP) transductant of human lung cancer cell line H460 (H460-GFP). The GFP-expressing lung cancer was visualized to metastasize widely throughout the skeleton when implanted orthotopically in nude mice. H460 was transduced with the pLEIN retroviral expression vector containing the enhanced GFP and the neomycin (G418) resistance gene. A stable high GFP-expressing clone was selected in vitro using 800 microg/ml G418. Stable high-level expression of GFP was maintained in s.c.-growing tumors formed after injecting H460-GFP cells in nude mice. To use H460-GFP for visualization of metastasis, fragments of s.c.-growing H460-GFP tumors were implanted by surgical orthotopic implantation in the left lung of nude mice. Subsequent micrometastases were visualized by GFP fluorescence in the contralateral lung, plural membrane, and widely throughout the skeletal system including the skull, vertebra, femur, tibia, pelvis, and bone marrow of the femur and tibia. The use of GFP-expressing H460 cells transplanted by surgical orthotopic implantation revealed the extensive metastatic potential of lung cancer in particular to widely disseminated sites throughout the skeleton. This new metastatic model can play a critical role in the study of the mechanism of skeletal and other metastasis in lung cancer and in screening of therapeutics that prevent or reverse this process.
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PMID:Widespread skeletal metastatic potential of human lung cancer revealed by green fluorescent protein expression. 976 40

Here, we report a fluorescent spontaneous bone metastatic model of human prostate cancer developed by surgical orthotopic implantation of green fluorescent protein (GFP)-expressing prostate cancer tissue. Human prostate cancer PC-3 cells were transduced with the pLEIN expression retroviral vector containing the enhanced GFP and neomycin resistance genes. Stable GFP high-expression PC-3 clones were selected in vitro with G418, which were then combined and injected s.c. in nude mice. For metastasis studies, fragments of a single highly fluorescent s.c. growing tumor were implanted by surgical orthotopic implantation in the prostate of a series of nude mice. Subsequent micrometastases and metastases were visualized by GFP fluorescence throughout the skeleton, including the skull, rib, pelvis, femur, and tibia The central nervous system, including the brain and spinal cord, was also involved with tumor, as visualized by GFP fluorescence. Systemic organs, including the lung, plural membrane, liver, kidney, and adrenal gland, also had fluorescent metastases. The metastasis pattern in this model reflects the bone and other metastatic sites of human prostate cancer. Thus, this model should be very useful for the study and development of treatment for metastatic androgen-independent prostate cancer.
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PMID:A fluorescent orthotopic bone metastasis model of human prostate cancer. 1002 62

We report here the establishment and metastatic properties of bright, highly stable, green fluorescent protein (GFP) expression transductants of the B16 mouse malignant melanoma cell line and the LOX human melanoma line. The highly fluorescent malignant melanoma cell lines allowed the visualization of skeletal and multiorgan metastases after i.v. injection of B16 cells in C57BL/6 mice and intradermal injection of LOX cells in nude mice. The melanoma cell lines were transduced with the pLEIN expression retroviral vector containing the GFP and neomycin resistance genes. Stable B16F0 and LOX clones expressing high levels of GFP were selected stepwise in vitro in levels of G418 of up to 800 microg/ml. Extensive bone and bone marrow metastases of B16F0 were visualized by GFP expression when the animals were sacrificed 3 weeks after cell implantation. Metastases for both cell lines were visualized in many organs, including the brain, lung, pleural membrane, liver, kidney, adrenal gland, lymph nodes, skeleton, muscle, and skin by GFP fluorescence. This is the first observation of experimental skeletal metastases of melanoma, which was made possible by GFP expression. These models should facilitate future studies of the mechanism and therapy of bone and multiorgan metastasis of melanoma.
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PMID:Genetically fluorescent melanoma bone and organ metastasis models. 1058 71

Here, we report the establishment of a stably transfected cell line which expresses high levels of green fluorescent protein (GFP), thus permitting the detection and visualization of developing tumors and lymph node metastases after injection into nude mice. Cells of the human oral squamous carcinoma cell line (SAS-L1) were transfected with an expression vector containing a cDNA encoding humanized GFP and the neomycin resistance gene. A clone with stable high-level expression of GFP was selected in vitro using G418. To study metastasis formation, GFP-expressing cells were injected orthotopically into the tongue of nude mice. The resultant tumor growth in the tongue and micrometastases in the lymph nodes could be visualized by GFP fluorescence. Therefore a useful model has been developed for the study of oral cancer, firstly to understand the metastatic process and secondly for the evaluation of potential treatments.
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PMID:Lymph node metastasis of oral cancer visualized in live tissue by green fluorescent protein expression. 1216 18

Bone sialoprotein (BSP) is a major non-collagenous protein found almost exclusively in bone and other mineralized tissues including enamel, dentin and cementum. Although a role for BSP in mineralization has been indicated, BSP also appears to function in patho-physiological processes, including the metastasis of breast and prostate cancer cells to bone. The purpose of this study was to determine the role of BSP in the homing of cancer cells and to provide insights into the role of BSP in physiological as well as pathological processes. We established cultures of MDA-231 breast cancer cells stably transfected with DNA constructs of pIRES2-EGFP (green fluorescent protein) expressing human BSP (hBSP) cDNA (231BSP) under a CMV promoter, or with an antisense sequence of hBSP cDNA (231BSPAS), or with an empty vector as a control (231EV). These 3 cell groups were selected for neomycin resistance using G418 and analyzed by flow cytometry for GFP expression. The resultant cultured cells expressed different levels of hBSP as detected by RT-PCR and Western blot. Among the three, 231BSP expressed the highest levels of hBSP while 231BSPAS expressed the lowest. The capacity of the tumor cells to metastasize to bone was determined in nude mice (5 in each group) by intra-cardiac injection of the cells from the 3 different groups. Four weeks after inoculation, radiological examination revealed that all the 5 mice in the 231BSP cell group had developed osteolytic bone metastases. In the 231BSPAS group only 1 mouse demonstrated metastatic bone lesions while 3 out of 5 mice in the control group (231EV) developed metastatic lesions in the bone. These results strongly suggest that BSP over-expression in human tumor cells can enhance bone metastasis of MDA-231 cells whereas repressed expression of BSP, using antisense BSP cDNA, inhibits this effect in a mouse model.
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PMID:Over-expression of bone sialoprotein enhances bone metastasis of human breast cancer cells in a mouse model. 1296 84

We have established stable, bright green fluorescent protein (GFP)- or red fluorescent protein (RFP)-expressing HT-1080 human fibrosarcoma clones. These cell lines showed similar cell proliferation rates and high-frequency experimental lung metastasis. The HT-1080-GFP and -RFP clones enable simultaneous real-time dual-color imaging in the live animal. HT-1080 cells were transduced with retroviral vectors containing GFP or RFP and the neomycin resistance gene. Stable transformants were selected stepwise with G418 up to 800 microl/ml. Subsequently, high GFP- or RFP-expressing clones, HT-1080-GFP or HT-1080-RFP, respectively, were selected. 3 x 10(6) cells from each clone were mixed and injected into the tail vein of SCID mice. The cells seeded the lung at high frequency with subsequent formation of pure green and pure red colonies as well as mixed yellow colonies with different patterns visualized directly on excised lungs. The lung metastases were also visualized by external fluorescence imaging in live animals through skin-flap windows over the chest wall. Lung metastases were observed on the lung surface of all mice. SCID mice well tolerated multiple surgical procedures for direct-view imaging via skin-flap windows. Real-time metastatic growth of the two different colored clones in the same lung was externally imaged with resolution and quantification of green, red, or yellow colonies in live animals. The color coding enabled determination of whether the colonies grew clonally or were seeded as a mixture with one cell type eventually dominating, or whether the colonies grew as a mixture. The simultaneous real-time dual-color imaging of metastatic colonies described in this report gives rise to the possibility of color-coded imaging of clones of cancer cells carrying various forms of gene of interest.
Clin Exp Metastasis 2003
PMID:Real-time imaging of individual fluorescent-protein color-coded metastatic colonies in vivo. 1466 94

Recently, it has been suggested that chemokine/receptor interactions determine the destination of the invasive tumor cells in several types of cancer. It has also been proposed that the stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system might be involved lymph node metastasis in oral squamous cell carcinoma (SCC). In order to further clarify the role of the SDF-1/CXCR4 system in oral SCC, we generated CXCR4 stable transfectants (IH-CXCR4) using oral SCC cells, and compared them to IH, which did not express CXCR4 and which did not have lymph node metastatic potentials in vivo. We introduced enhanced green fluorescent protein (GFP) fused-CXCR4 into IH cells, and detected the GFP fluorescence in the cytoplasm and cell membrane in approximately 60% of the G418-resistant cells. This bulk-transfectant expressed a high level of CXCR4 mRNA and protein, and exhibited the characteristic calcium fluxes and chemotactic activity observed in treatment with SDF-1. SDF-1 biphasically activated extracellular signal-regulated kinase (ERK)1/2, but continuously activated Akt/protein kinase B (PKB) in IH-CXCR4 cells. Most importantly, IH-CXCR4 cells frequently metastasized to the cervical lymph node, but not to the distant organs in the orthotopic inoculation of nude mice. Furthermore, these lymph node metastases were inhibited by the treatment of a mitogen-activated protein kinase/ERK kinase inhibitor, U0126, or a phosphatidylinositol 3 kinase inhibitor, wortmannin. These results indicate that SDF-1/CXCR4 signaling mediates the establishment of lymph node metastasis in oral SCC via ERK1/2 or Akt/PKB pathway.
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PMID:Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma. 1549 52

To understand the mechanisms underlying bone marrow metastasis precisely, we established the highly metastatic 4T1E/M3 murine breast cancer cell line. 4T1 murine breast cancer cells were transfected with the neomycin resistance gene, selected in G418, intravenously injected into mice, and harvested from bone marrow. By repeating this protocol three times, we established the 4T1E/M3 cells. The clonality of 4T1E/M3 cells was markedly high confirmed by genomic southern analysis using neo-gene probe. When tissues harvested from mice after intravenous injection of 4T1E/M3 cells were examined histologically, markedly enhanced bone marrow metastasis was observed; 77% of spines from 4T1E/M3-injected mouse showed metastasis as compared to 14% metastasis seen with the parent cells. In vitro, 4T1E/M3 cells attached more strongly to the plastic plate and to bone marrow-derived endothelial cells. DNA micro arrays, real time RT-PCR and FACS analyses revealed that the expression of ICAM-1 and beta2 integrin was upregulated in 4T1E/M3 cells at both the mRNA and cell surface protein levels. 4T1E/M3 cells also showed greater anchorage-independent proliferation in soft agar, and migrated markedly faster than the parent cells in wound healing assays. Anti-ICAM-1 antibodies strongly inhibited both the colony formation and the migration activity of 4T1E/M3 suggesting the importance of the role of ICAM-1. Our newly established highly metastatic 4T1E/M3 cells may provide a potentially powerful tool to study the molecular mechanisms of bone marrow metastasis and to identify new molecular targets for therapeutic interventions.
Clin Exp Metastasis 2008
PMID:A highly bone marrow metastatic murine breast cancer model established through in vivo selection exhibits enhanced anchorage-independent growth and cell migration mediated by ICAM-1. 1834 Apr 24

Ectopic expression of MCAM/MUC18, a cell adhesion molecule in the immunoglobulin-like gene superfamily, induces two moMCAM/MUC18-minus, non-metastatic mouse melanoma K1735 sublines, K3 (tumor+/metlow) and K10 (tumor-/metlow), to metastasize to lungs in a syngeneic C3H mouse model. In this report, we extended investigation of effects of moMCAM/MUC18 expression on tumorigenesis and metastasis in another lowly metastatic, however highly tumorigenic moMCAM/MUC18-minus mouse melanoma K1735 subline, K9 (tumor+++/metlow). We transfected this subline with the moMCAM/MUC18 cDNA, selected for G418-resistant clones with different expression levels of moMCAM/MUC18, and used them for testing effects of MCAM/MUC18 expression on in vitro growth rate, motility, and invasiveness, in vivo subcutaneous tumor growth, and pulmonary metastasis in syngeneic C3H brown mice. Similar to K3 and K10 cells, increased expression of MCAM/MUC18 in K9 cells did not significantly affect in vitro growth rate, but increased in vitro motility and invasiveness. Surprisingly, increased expression of MCAM/MUC18 in K9 cells decreased their induction of tumorigenesis and suppressed their establishment of pulmonary nodules in syngeneic C3H brown mice. We concluded that increased MCAM/MUC18 expression in K9 subline increased in vitro epithelial-to-mesenchymal transition; however, it suppressed in vivo tumorigenicity and metastasis. Thus MCAM/MUC18 acts as a tumor and metastasis suppressor for the K9 subline, different from its role in other K1735 sublines, K3 and K10. Different intrinsic co-factors in different K1735 sublines, which modulate the functions of MCAM/MUC18 in the cells that interact differently to the tumor microenvironment, may render sublines manifest differently in tumorigenicity and metastasis in vivo.
Clin Exp Metastasis 2016 12
PMID:Ectopic expression of MCAM/MUC18 increases in vitro motility and invasiveness, but decreases in vivo tumorigenesis and metastasis of a mouse melanoma K1735-9 subline in a syngeneic mouse model. 2751 May 63


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